PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA
再生障碍性贫血的发病机制和治疗
基本信息
- 批准号:6432684
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:aplastic anemia artificial immunosuppression autoimmune disorder bone marrow disorder clinical research cytotoxic T lymphocyte gene targeting hematopoiesis hematopoietic stem cells hepatitis histocompatibility typing human subject human therapy evaluation immunohematology lymphokines paroxysmal nocturnal hemoglobinuria phosphatidylinositols tissue /cell culture
项目摘要
Aplastic anemia (AA) and other types of bone marrow failure have clinical and laboratory features consistent with an autoimmune pathophysiology, with a diversity of inciting antigens, including viruses, chemicals, and drugs. Whatever its specific etiology, a majority of patients respond with hematologic improvement after immunosuppressive therapies. One important clinical feature of AA is its evolution, sometimes years after normalization of blood counts, to other hematologic diseases such as paroxysmal nocturnal hemoglobinuria (PNH), which derive from clones of hematopoietic stem cells. Our laboratory studies have focused on the immune pathophysiology of AA, identification of a viral antigen, and the mechanism of late clonal evolution. Studies of etiology have continued to focus on an unknown hepatitis virus in the post-hepatitis AA syndrome (see Z01 HL 02319-14 HB). Current studies of the immune systems role in bone marrow suppression have focused on gamma-interferon (gamma-IFN), a lymphokine that inhibits hematopoiesis in vitro and in vivo. In our animal model for immune-mediated AA, congenic lymphocytes induce profound marrow aplasia, which can be abrogated by early administration of anti- lymphocyte globulin (ATG), cyclosporine, and monoclonal antibody to gamma-IFN. Current efforts are directed to producing chronic aplasia by periodic infusions of lymphoid cells, as well as determination of the specificity of the immune response. We have measured gamma-IFN in circulating and marrow lymphocytes using flow cytometry. About 2/3 of patients with severe AA and also with the diagnosis of hypocellular myelodysplasia shown the presence of this cytokine in blood T cells; less than 10% of recovered patients scored positive. The presence of the cytokine was highly predictive for response to immunosuppressive therapies: 16/16 patients whose cells contained gamma-IFN responded, compared to 4/12 patients whose blood lacked gamma-IFN; IFN declined after treatment, while IL-4 content increased. Recurrence of IFN intracellularly predicted relapse. Marrow intracellular IFN may be even better correlated with response. Measurement of surface gamma-IFN allows isolation of viable activated T cells, which may be useful in determining lymphoid clonality and characterizing and even identifying their antigens. Intracellular cytokine measurements indicating TH1/TH2 balance are also altered by in vitro treatment with cyclosporine, various androgen preparations, and growth factor combinations; stem cell factor and granulocyte colony stimulating factor also depress IFN expression in vivo in normal individuals undergoing stem cell mobilization. In other clinical studies in aplastic anemia, 24 patients with newly diagnosed severe aplastic anemia have now been randomized in a comparative protocol; the response rate has been higher for ATG than for high dose cyclophosphamide, but frank relapses and cytogenetic abnormalities have occurred only in the ATG arm. For children, our standard protocol has been modified to shorten the duration of cyclosporine therapy, begin cyclosporine is begun later in order to avoid abrogation of ATG tolerization, and the new immunosuppressive agent mycophenolate mofetil has been added, all in an effort to decrease the high relapse rate. In the laboratory, late clonal disease, both PNH and myelodysplasia, using sensitive flow cytometric and fluorescent in situ hybridization assays. Approximately 20% of patients with AA and probably a larger proportion of cases of hypocellular myelodysplasia present with evidence of a PNH clone. Our results are consistent with the hypothesis that PNH represents an escape mechanism in immune-mediated bone marrow failure, and that two steps are required for the development of PNH. Alternatively, a glycosylphosphoinositol- linked protein may be involved in the initial antigenic stimulation. - autoimmunity, T cells, bone marrow failure, myelodsyplasia, immunosuppression, interferon - Human Subjects
再生障碍性贫血(AA)和其他类型的骨髓衰竭具有与自身免疫病理生理学一致的临床和实验室特征,具有多种激发抗原,包括病毒,化学品和药物。无论其具体病因如何,大多数患者在免疫抑制治疗后血液学改善。AA的一个重要临床特征是其演变,有时在血细胞计数正常化后数年,演变为其他血液学疾病,如阵发性睡眠性血红蛋白尿症(PNH),其来源于造血干细胞的克隆。我们的实验室研究主要集中在AA的免疫病理生理学、病毒抗原的鉴定和晚期克隆进化的机制上。病因学研究继续关注AA肝炎后综合征中的未知肝炎病毒(见Z 01 HL 02319-14 HB)。目前对免疫系统在骨髓抑制中的作用的研究集中在γ-干扰素(γ-IFN),一种在体外和体内抑制造血的淋巴因子。在我们的免疫介导的AA动物模型中,同源淋巴细胞诱导严重的骨髓再生障碍性贫血,这可以通过早期给予抗淋巴细胞球蛋白(ATG)、环孢菌素和γ-IFN单克隆抗体来消除。目前的努力是针对通过定期输注淋巴细胞以及确定免疫应答的特异性来产生慢性再生障碍。我们用流式细胞术测量了循环和骨髓淋巴细胞中的γ-IFN。约2/3的重度AA患者以及诊断为细胞减少性骨髓增生异常的患者显示血液T细胞中存在这种细胞因子;不到10%的康复患者评分为阳性。细胞因子的存在高度预测免疫抑制治疗的反应:16/16例细胞含有γ-IFN的患者有反应,而4/12例血液缺乏γ-IFN的患者有反应;治疗后IFN下降,而IL-4含量增加。IFN细胞内复发预测复发。骨髓细胞内干扰素可能与反应更好地相关。表面γ-IFN的测量允许活的活化T细胞的分离,其可用于确定淋巴克隆性和表征,甚至鉴定其抗原。细胞内细胞因子的测量表明TH 1/TH 2平衡也改变了体外治疗与环孢素,各种雄激素制剂,生长因子的组合,干细胞因子和粒细胞集落刺激因子也抑制干扰素的表达在体内正常人进行干细胞动员。在再生障碍性贫血的其他临床研究中,24名新诊断的重型再生障碍性贫血患者现在已经被随机分配到一个比较方案中; ATG的反应率高于高剂量环磷酰胺,但仅在ATG组中出现明显的复发和细胞遗传学异常。对于儿童,我们的标准方案已被修改以缩短环孢霉素治疗的持续时间,开始环孢霉素是为了避免废除ATG耐受,并已加入新的免疫抑制剂吗替麦考酚酸酯,所有这些都是为了降低高复发率。在实验室,晚期克隆性疾病,PNH和骨髓增生异常,使用敏感的流式细胞术和荧光原位杂交检测。大约20%的AA患者和可能更大比例的低细胞性骨髓增生异常病例存在PNH克隆的证据。我们的研究结果是一致的假设,即PNH代表免疫介导的骨髓衰竭的逃逸机制,PNH的发展需要两个步骤。或者,糖基磷酸肌醇连接蛋白可能参与初始抗原刺激。- 自身免疫、T细胞、骨髓衰竭、骨髓增生异常、免疫抑制、干扰素-人类受试者
项目成果
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{{ truncateString('NEAL S YOUNG', 18)}}的其他基金
Immune Pathophysiology of Aplastic Anemia and Immunosuppressive Treatments
再生障碍性贫血的免疫病理生理学和免疫抑制治疗
- 批准号:
8746560 - 财政年份:
- 资助金额:
-- - 项目类别:
Immune Pathophysiology of Aplastic Anemia and Immunosuppressive Treatments
再生障碍性贫血的免疫病理生理学和免疫抑制治疗
- 批准号:
9157323 - 财政年份:
- 资助金额:
-- - 项目类别:
Immune Pathophysiology of Aplastic Anemia and Immunosuppressive Treatments
再生障碍性贫血的免疫病理生理学和免疫抑制治疗
- 批准号:
10685871 - 财政年份:
- 资助金额:
-- - 项目类别:
Immune Pathophysiology of Aplastic Anemia and Immunosuppressive Treatments
再生障碍性贫血的免疫病理生理学和免疫抑制治疗
- 批准号:
8149485 - 财政年份:
- 资助金额:
-- - 项目类别: